Saturday , November 18 2017
Home / Therapies / Alpha-glucosidase Therapy Center / Mechanisms and Receptors Controlling Intestinal GLP-1 Secretion, Part 2

Mechanisms and Receptors Controlling Intestinal GLP-1 Secretion, Part 2

David Joffe, BSPharm, CDE 
Brittany Davis, Pharm D Candidate, Presbyterian College School of Pharmacy

The molecular mechanisms linking fatty acids to GLP-1 secretion from gut endocrine cells remain incompletely understood. Hirasawa and colleagues have identified a GPCR, designated GPR120 that serves as a receptor for fatty acids on gut endocrine cells. Fatty acids activate the receptor in vitro in association with stimulation of GLP-1 secretion. Whether GPR120 is essential for fatty acid-stimulated GLP-1 secretion in vivo remains unclear.1….

See more GLP-1 Agonist Resources

A role for PKCz in the oleic acid-induced stimulation of GLP-1 secretion has been described in studies using gut endocrine cells. Reduction of PKCz expression in GLUTag cells, or addition of a PKCz inhibitor significantly diminished the secretory response to oleic acid.2

Daoudi and colleagues, using a variety of experimental cellular and animal models, have demonstrated that activation of the PPARb/d receptor, promotes GLP-1 synthesis and secretion from gut endocrine cells. Increasing levels of glucose induced expression of the proglucagon and PC1/2 genes but not the genes for GBAR1/TGR5 nor the PPARb/d receptor in GLUTag cells. PPARg activation with rosiglitazone decreased proglucagon mRNA, however, the PPARb/d agonist GW501516 significantly increased (2-4-fold) proglucagon gene expression and GLP-1 secretion in GLUTag cells and in human NCI-H716 cells. Knockdown of PPARb/d using siRNA completely eliminated the effect of PPARb/d agonists on proglucagon gene expression. Treatment of jejunal tissue obtained from obese human subjects with GW51056 for 24 hrs induced proglucagon gene expression and enhanced glucose- and bile acid-stimulated GLP-1 release. PPARb/d agonists also increased the activity of proglucagon promoter plasmids in transfected GLUTag cells through mechanisms requiring TCF4. GW0742, another PPARb/d agonist, increased intestinal but not pancreatic proglucagon gene expression in WT mice but not in PPARb/d-/- mice. Intriguingly, GLP-1 receptor mRNA transcripts were also increased in the pancreas of GW501516-treated mice and in isolated human islets. Furthermore, mice treated with PPARb/d agonists exhibited increased levels of GLP-1 and insulin and improved glycemia following oral glucose challenge. Similar salutary effects on GLP-1 levels and glucose tolerance were also observed in ob/ob mice treated with PPARb/d agonists.3

Studies using knockout mice and GLUTag cells have demonstrated a role for synaptogamin-7 as a molecular component of the exocytotic machinery regulating GLP-1 secretion in L cells. Synaptogamin-7 KO mice exhibited defective GLP-1 secretion in response to oral glucose and knockdown of synaptogamin-7 in GLUTag L cells reduced GLP-1 secretion in vitro.4

Similar studies using the STC-1 cell line have identified a receptor for bile acids, designated TGR5 (also known as BG37) which is coupled to stimulation of GLP-1 secretion in a cAMP-dependent manner.5 Subsequent studies have demonstrated that TGR5 agonists improve glucose homeostasis in mice, through mechanisms that are associated with enhanced GLP-1 secretion from gut endocrine L cells, and increased GLP-1 secretion in mice treated with TGR5 agonists.6 Parker and colleagues examined the mechanisms through which bile acids promoted GLP-1 secretion in enteroendocrine GLUTag cells in a TGR5-dependent manner. Bile acids stimulated GLP-1 secretion from GLUTag cells in a TGR5-dependent manner. The synthetic TGR5 agonist GPBAR-A increased levels of cAMP and potentiated glucose-stimulated signal transduction in GLUTag cells.7

Furthermore, breakdown of fats is an essential upstream event, directly or indirectly, for subsequent stimulation of GLP-1 secretion in human subjects. Duodenal infusion of a triglyceride emulsion stimulated CCK and GLP-1 secretion; the same infusion carried out in the presence of the lipase inhibitor tetrahydrolipstatin resulted in attenuation of pyloric pressures, increased number of antral and duodenal pressure waves, and elimination of the fat-induced rise in circulating levels of CCK and GLP-1. Similarly, human diabetic subjects given the lipase inhibitor orlistat in the presence of an olive oil and glucose drink exhibit reduced gastric emptying, increased glycemic excursion, and decreased levels of circulating GLP-1.8

Whether the stimulation of CCK/GLP-1 secretion is due directly to generation of fatty acids, or partly due to the complex integration of fatty acids and patterns of gut motility/pressure, warrants further investigation.9

Experiments using murine GLUTag cells have identified a role for glutamine as a potential chemical mediator of GLP-1 secretion from enteroendocrine cells.10 Acute oral administration of glutamine also increases plasma levels of GLP-1 in human subjects, with or without diabetes.11 Further analysis of the effects of amino acids and glutamine on GLP-1 secretion in GLUTag cells and non-immortalized murine L cells was reported by Tolhurst and colleagues. Glutamine stimulated GLP-1 secretion from murine L cell cultures in a dose-dependent manner, similar to previous observations made using GLUTag cells. GLP-1 secretion was also stimulated by other amino acids, although glutamine produce the most potent effects. Glutamine increased intracellular calcium through mechanisms requiring extracellular calcium and Na+ transport. In contrast, the metabolic derivative glucosamine failed to stimulate GLP-1 release, and the mTOR pathway did not appear to be involved as the effects of Gln were not sensitive to rapamycin, nor inhibitors of PKC or thapsigargin. Notably, glutamine triggered cAMP accumulation. The precise membrane transporter/receptor mediating the stimulatory effects of Gln on the L cell remains to be determined.12

Flock and colleagues identified robust expression of the classical progesterone receptor in GLUTag cells and showed that enteral progesterone stimulates GLP-1 secretion and lowers blood glucose in mice. Remarkably, membrane restricted ligands such as BSA-progesterone also stimulated GLP-1 secretion from GLUTag cells, and inhibition of classical PR signaling with RU486 had no effect on progestin-stimulated GLP-1 secretion and did not impair the ability of progesterone to improve glucose homeostasis in vivo. GLUTag cells also expressed membrane progesterone receptors Paqr5 and Paqr7, and knockdown of these receptors in GLUTag cells eliminated the progestin-dependent stimulation of GLP-1 secretion. Nevertheless, enteral progesterone was still capable of increasing insulin and lower glucose even in mice with disruption of both the Glp1r and Gipr. These findings raise the possibility that gut restricted membrane progesterone receptor agonists may be capable of enhancing incretin secretion and lowering glucose in vivo.13

Studies in the rat identify an important role for muscarinic receptors in the control of meal-stimulated GLP-1 release. Both atropine, and pirenzepine, a M1 muscaranic receptor antagonist) block fat-induced GLP-1 secretion in vivo, and muscaranic receptors are expressed on rodent L cells.14 The importance of the sympathetic (inhibitory) and cholinergic (stimulatory) nervous system for control of gut PGDP secretion was further illustrated in studies employing the isolated perfused pig intestine together with specific agonist and antagonists of the respective neurotransmitters.15

GPR119 was originally described as an orphan G protein coupled receptor that was subsequently demonstrated to be expressed in human and rodent gut endocrine cells, and in GLUTag cells. Activation of GPR119 signaling, presumably in enteroendocrine cells in vivo, leads to increased secretion of gut hormones such as GIP and GLP-1 as demonstrated by Chu and colleagues. Although GPR119 agonists stimulate the secretion of both GLP-1 and GIP in mice, the actions on GIP secretion may be indirect, as GPR119 receptors have not yet been detected on GIP+ gut enteroendocrine K cells.16

The levels of intracellular cAMP appear to be important for regulation of intestinal GLP-1 synthesis and secretion. Studies using primary rat intestinal cell cultures, intestinal enteroendocrine cell lines, and multiple cis-acting domains have shown that activation of the adenylate cyclase pathway induces proglucagon gene transcription and GLP-1 biosynthesis.17,18,19 This pathway also co-regulates the expression of the enzyme, PC1, that plays an important role in liberation of GLP-1 from proglucagon in gut L cells.20

The local production of somatostatin-28 may also regulate, via inhibition, the tonic release of GLP-1 and GLP-2 from gut L cells, as illustrated by immunoneutralization studies in the perfused porcine ileum.21 As GLP-1 stimulates SMS release from intestinal cells, it appears that SMS and GLP-1 may constitute an autoregulatory loop, with GLP-1 secretion attenuated following stimulation of intestinal SMS release.22, 23 The somatostatin receptor subtype 5 seems to be particularly important for control of intestinal GLP-1 secretion in rat intestinal cell cultures.23. Insulin may play a role in the tonic stimulation of GLP-1 secretion, as preclinical studies demonstrate that insulin may stimulate GLP-1 secretion, raising the possibility that insulin resistance may contribute to defective GLP-1 secretion.24 Leptin was also shown to be important for the control of GLP-1 secretion by Brubaker and colleagues.25

The available data in rodents supports a role for GPR40 (FFA1) as an enteroendocrine fatty acid GPCR linked to GLP-1 secretion. Original studies carried out by Edflak and colleagues in mice have since been confirmed by others.26 Xiong and colleagues identified co-localization of a FFA reporter gene and GLP-1 immunoreactive GLP-1 in mouse small bowel enteroendocrine cells. Corn oil administration (enteral) stimulated an increase in plasma GLP-1 levels in GPR120-/- but not in FFA1-/- mice and glycemic excusrion was higher after corn oil in Glp1r-/- mice. Long chain fatty acids and synthetic FFA1 ligands directly increased GLP-1 secretion from FMIC cultures and GLUTag cells in vitro. Evidence using partial and full agonists supports a mechanism involving alloesteric interactions necessary for full glucoregulatory potential in murine systems.27 Whether activation of GPR40/FFA1 increases GLP-1 secretion in humans requires more study.

Prostaglandins are locally synthesized in the gastrointestinal tract and Coskun and colleagues demonstrate the expression of the EP4 prostanoid receptor in enteroendocrine GLUTag cells. Prostaglandin E1 and E2 as well as more selective EP4 receptor agonists stimulated GLP-1 secretion from GLUTag cells in vitro, and in mice in vivo. Surprisingly however, the EP4 agonists also raised blood glucose in acute glucose tolerance tests, despite increasing plasma levels of GLP-1 in mice.28

The bone-derived hormone osteocalcin (uncarboxylated form) has also been shown to increase GLP-1 secretion from STC-1 cells through its ‘putative’ receptor Gprc6a at most but not all doses in vitro, and plasma active GLP-1 levels increased following injection of 7 but not 10 ug/kg of recombinant u-osteocalcin protein in fasted mice in the presence of co-administered sitagliptin. Remarkably, oral administration of various osteocalcin proteins also increased GLP-1 levels in mice. Osteocalcin also increased serum insulin levels in fasted mice through mechanisms sensitive to the GLP-1R antagonist exendin.29

Drugs and plasma levels of GLP-1

Several studies using the drug acarbose have shown increased circulating levels of GLP-1 in association with short or longer term acarbose use in human subjects. Acarbose inhibits the action of glucosidases, thus diminishing carbohydrate absorption in the proximal intestine, and increasing delivery of complex carbohydrates to the distal intestine. Acarbose ingestion along with sucrose prolongs the kinetics of “second phase” GLP-1 secretion in human subjects.30 Acarbose administration also prolongs time to gastric emptying, possibly due in part to enhanced GLP-1 release.31, 32

Similar elevations in circulating GLP-1 following acarbose ingestion have also been observed in some but not all studies of patients with Type 2 diabetes.33 Nevertheless, it should not be assumed that acarbose administration is always associated with enhanced GLP-1 release, as no significant evidence for enhanced GLP-1 release in the setting of acarbose administration was detected in subjects over the age of 65 with Type 2 diabetes.34 In contrast, acute and prolonged treatment with acarbose was not associated with increased plasma levels of GLP-1 in studies of 10 patients with Type 2 diabetes before and after single and repeat 2 week dosing (100 mg t.i.d).35


Patients receiving metformin have also been noted to exhibit additive glucose lowering benefits following institution of GLP-1 therapy.36 In a study of 10 obese non-diabetic male patients, metformin administration was associated with increased levels of circulating GLP-1 following oral glucose-loading, and in experiments using pooled human plasma, metformin (0.1-0.5 ug/ml) significantly inhibited degradation of GLP-1(7-36)amide after a 30-min incubation at 37 degrees C, in the presence or absence of DPP-4. The authors of this study raised the possibility that metformin may inhibit the enzymatic breakdown of GLP-1 both in vitro and in vivo.37

A subsequent study examined the interaction between metformin, DPP-4, and GLP-1 degradation using biochemical analyses in vitro. Demuth and colleagues found no effect of metformin on the DPP-4-mediated degradation of GLP-1 using a variety of sources of human DPP-4.38 Nevertheless, the observation that administration of metformin and related biguanides increases plasma levels of GLP-1 has also been made in wildtype rats or Fischer rats with inactivating DPP-4 mutation.39

Similarly, combination therapy with both metformin and the DPP-4 inhibitor Val-Pyr produces a synergistic anti-diabetic effect, including increased levels of plasma GLP-1, and a reduction in food intake and weight loss, beyond that seen with either agent alone when administered to Zucker fa/fa rats for 14 days.40

Migoya and colleagues examined GLP-1 synthesis and secretion in mice with diet-induced obesity and plasma levels of GLP-1 and GIP were also assessed in non-diabetic human subjects following acute metformin administration. Metformin administered to high fat fed mice by oral gavage acutely increased total GLP-1 immunoreactivity in both fasted and fed mice within 1 hr post dosing and increased levels of proglucagon mRNA transcripts were detected in the mouse large bowel even 1 hr after metformin administration, whereas no effect of metformin on pancreatic proglucagon mRNA transcripts was observed. Similarly, metformin increased plasma GLP-1 levels (total GLP-1 immunoreactivity) in healthy non-diabetic subjects whereas sitagliptin alone decreased total GLP-1 levels but increased active GLP-1 levels. In contrast, metformin had no effect on circulating GIP levels in human subjects.41

Similar findings in rodents were reported by Maida et al who demonstrated acute increases in plasma levels of GLP-1 following metformin administration to fasted mice, but no effect on circulating levels of GIP. Although the AMPK activator AICAR also acutely and markedly increased GLP-1 levels in mice, the mechanism through which metformin promotes GLP-1 secretion appears indirect and has not yet been precisely elucidated. Notably metformin also increased islet incretin receptor expression via a PPARy-dependent mechanism in both cells and mice and directly enhanced the insulinotropic actions of incretin hormones. The actions of metformin to induce islet incretin receptor expression were absent in PPARy-/- mice.42, 43

The actions of metformin to acutely stimulate GLP-1 secretion in rats appear to be indirect, requiring M3 muscarinic receptors and GRP. In contrast, Mulherin and colleagues did not find any direct effect of metformin to stimulate GLP-1 secretion from GLUTag, NCH-H716, or rat FRIC cultures.44

Gastric bypass surgery, GLP-1, and weight loss

As many patients with obesity experience rapid weight loss together with striking amelioration of their diabetes often within days of gastric bypass surgery, a role for GI hormones such as GLP-1 has been invoked to explain these impressive clinical improvements. Valverde and colleagues studied plasma levels of GLP-1, together with serial analysis of glucose tolerance in two groups of patients; after Larrad’s pancreaticobiliary diversion (BPD) or following vertical banded gastroplasty (VBG). Basal and glucose-stimulated plasma GLP-1 increased after surgery, with GLP-1 levels comparatively greater in subjects following BPD.45 Similar results were found in patients following gastric bypass surgery.46, 47

The observation that some patients treated with gastric bypass exhibit hypoglycemia and neuroglycopenia has raised the questions as to whether exaggerated incretin responses underlie this problem in some patients. Goldfine and colleagues have reported a cross-sectional analysis of incretin secretory profiles in patients post gastric bypass with and without symptoms of hypoglycemia. Plasma levels of GLP-1 are clearly very significantly increased in some patients with hypoglycemia post GBP.48


Glucocorticoids are known to induce insulin resistance and impair beta-cell function. Hansen et al administered a high fat diet and prednisolone 37.5 mg/day for 12 days, then examined incretin secretion and glucose responses. Plasma glucose responses to a test meal increased modestly, with increases in glucagon, insulin, and GIP, but no changes in plasma GLP-1 observed in response to a test meal.49


Administration of the Sirt1 activator resveratrol has been shown to increase GLP-1 synthesis and GLP-1 secretion and improve glucose homeostasis via a GLP-1R-dependent manner in mice.50 The explanation for these findings, confirmed by Park and colleagues, appears to reflect the ability of resveratrol to increase cAMP via inhibition of phosphodiesterase activity, consistent with the potent properties of cyclic AMP to stimulate PGDP biosynthesis and GLP-1 secretion from L cells.51

GLP-1 clearance

There appear to be two principal mechanisms responsible for regulating the levels of intact GLP-1 in the circulation, namely N-terminal cleavage at the position 2 alanine by DPP-4, and renal elimination. There are several studies demonstrating the importance of the kidney in GLP-1 clearance. The clearance of GLP-1 is significantly altered in nephrectomized dogs and studies in human subjects with chronic renal failure demonstrate the importance of the kidney for clearance and degradation of both GLP-1 and GIP.52, 53


1.    Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med. 2005 Jan;11(1):90-4. Epub 2004 Dec 26

2.    Protein kinase C{zeta} is required for oleic acid-induced secretion of glucagon-like peptide-1 by intestinal endocrine L cells. Endocrinology. 2006 Nov 16;in press

3.    PPARβ/δ Activation Induces Enteroendocrine L Cell GLP-1 Production Gastroenterology. 2011 Feb 4

4.    Synaptotagmin-7 as a positive regulator of glucose-induced glucagon-like peptide-1 secretion in mice Diabetologia. 2011 Mar 22. [Epub ahead of print]

5.    Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun. 2005 Apr 1;329(1):386-390.

6.    TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009 Sep;10(3):167-77.

7.    Molecular mechanisms underlying bile acid stimulated glucagon-like peptide-1 secretion. Br J Pharmacol. 2011 Jun 30. doi: 10.1111/j.1476-5381.2011.01561.x. [Epub ahead of print

8.    Effect of lipase inhibition on gastric emptying of, and the glycemic and incretin responses to, an oil/aqueous drink in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2003 Aug;88(8):3829-34.

9.    Effects of fat digestion on appetite, APD motility, and gut hormones in response to duodenal fat infusion in humans. Am J Physiol Gastrointest Liver Physiol. 2003 May;284(5):G798-807

10. Glutamine potently stimulates glucagon-like peptide-1 secretion from GLUTag cells. Diabetologia. 2004 Sep 9.

11. Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects Am J Clin Nutr. 2009 Jan;89(1):106-13.

12. Glutamine Triggers and Potentiates Glucagon-Like Peptide-1 Secretion by Raising Cytosolic Ca2+ and cAMP Endocrinology. 2011 Jan 5. [Epub ahead of print

13. Activation of Enteroendocrine Membrane Progesterone Receptors Promotes Incretin Secretion and Improves Glucose Tolerance in Mice Diabetes. 2012 Aug 29.

14. Muscarinic receptors control postprandial release of glucagon-like Peptide-1: in vivo and in vitro studies in rats. Endocrinology. 2002 Jun;143 (6): 2420-6.

15. Neural regulation of glucagon-like peptide-1 secretion in pigs. Am J Physiol Endocrinol Metab. 2004 Nov;287(5):E939-47

16. A Role for Intestinal Endocrine Cell-Expressed GPR119 in Glycemic Control by Enhancing GLP-1 and GIP Release Endocrinology. 2008 Jan 17; [Epub ahead of print].

17. Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine. Proc Natl Acad Sci U S A. 1989 Jun;86(11):3953-7

18. Activation of proglucagon gene transcription by protein kinase-A in a novel mouse enteroendocrine cell line. Mol Endocrinol. 1994 Dec;8(12):1646-55

19. Multiple cis-acting domains mediate basal and adenosine 3′,5′-monophosphate-dependent glucagon gene transcription in a mouse neuroendocrine cell line. Endocrinology. 1993 Mar;132(3):1055-62

20. Coregulation of Glucagon-Like Peptide-1 Synthesis with Proglucagon and Prohormone Convertase 1 Gene Expression in Enteroendocrine GLUTag Cells. Endocrinology. 2001 Jan 1;142(1):37-42

21. Am J Physiol 2000 ;278(6):E1010-E1018.

22. Endocrinology. 1998 Jan;139(1):148-55

23. Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures. Am J Physiol Endocrinol Metab. 2002 Aug;283(2):E311-7

24. Insulin regulates glucagon-like peptide-1 secretion from the enteroendocrine L cell. Endocrinology. 2008 Sep 25. [Epub ahead of print].

25. Role of leptin in the regulation of glucagon-like Peptide-1 secretion. Diabetes. 2003 Feb;52(2):252-9

26. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion Diabetes. 2008 Sep;57(9):2280-7

27. Activation of FFA1 mediates GLP-1 secretion in mice. Evidence for allosterism at FFA1 Mol Cell Endocrinol. 2013 Feb 9. doi:pii: S0303-7207(13)00032-4.

28. Activation of Prostaglandin E Receptor 4 Triggers Secretion of Gut Hormone Peptides GLP-1, GLP-2, and PYY Endocrinology. 2012 Nov 9. [Epub ahead of print]

29. Osteocalcin induces release of glucagon-like Peptide-1 and thereby stimulates insulin secretion in mice PLoS One. 2013;8(2):e5737

30. Glucagon-like peptide 1 (7-36 amide) secretion in response to luminal sucrose from the upper and lower gut. A study using alpha-glucosidase inhibition (acarbose). Scand J Gastroenterol. 1995 Sep;30(9):892-6.

31. Delayed gastric emptying occurs following acarbose administration and is a further mechanism for its anti-hyperglycaemic effect. Diabet Med. 1998 Feb;15(2):120-4

32. Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release. Am J Physiol Gastrointest Liver Physiol. 2001 Sep;281(3):G752-63.

33. Prolonged and enhanced secretion of glucagon-like peptide 1 (7-36 amide) after oral sucrose due to alpha-glucosidase inhibition (acarbose) in Type 2 diabetic patients. Diabet Med. 1998 Jun;15(6):485-91.

34. Glucagon-like peptide-1 response to acarbose in elderly type 2 diabetic subjects. Diabetes Res Clin Pract. 2002 May;56(2):101-6.

35. Alpha-Glucosidase inhibition (acarbose) fails to enhance secretion of glucagon-like peptide 1 (7-36 amide) and to delay gastric emptying in Type 2 diabetic patients. Diabet Med. 2005 Apr;22 (4): 470-6

36. Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes. Diabetes Care. 2001 Apr;24(4):720-5.

37. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care. 2001 Mar;24(3):489-94

38. Metformin Effects on Dipeptidylpeptidase IV Degradation of Glucagon-like Peptide-1. Biochem Biophys Res Commun. 2002 Mar 15;291(5):1302-8.

39. Enhanced secretion of glucagon-like peptide 1 by biguanide compounds. Biochem Biophys Res Commun. 2002 Nov 15;298(5):779-84.

40. Metformin causes reduction of food intake and body weight gain, and improvement of glucose intolerance in combination with dipeptidyl peptidase IV inhibitor in Zucker fa/fa rats. J Pharmacol Exp Ther. 2004 Mar 23 [Epub ahead of print]

41. Dipeptidyl Peptidase-4 Inhibitors Administered in Combination With Metformin Result in an Additive Increase in the Plasma Concentration of Active GLP-1 Clin Pharmacol Ther. 2010 Nov 3.

42. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice Diabetologia 2011 Feb;54(2):339-49.

43. New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser Diabetologia 2011 Feb;54(2):219-22

44. Mechanisms Underlying Metformin-Induced Secretion of Glucagon-Like Peptide-1 from the Intestinal L Cell Endocrinology October 4, 2011, doi: 10.1210/en.2011-1485

45. Changes in glucagon-like peptide-1 (GLP-1) secretion after biliopancreatic diversion or vertical banded gastroplasty in obese subjects. Obes Surg. 2005 Mar;15(3):387-97

46. GLP-1, PYY, Hunger and Satiety Following Gastric Bypass Surgery In Morbidly Obese Subjects. J Clin Endocrinol Metab. 2006 Feb 14; [Epub ahead of print]

47. Incretin levels and effect are markedly enhanced one month after Roux-en-Y gastric bypass surgery in obese patients with type 2 diabetes. Diabetes Care. 2007 Apr 6; [Epub ahead of print]

48. Patients with Neuroglycopenia Post Gastric Bypass Surgery Have Exaggerated Incretin and Insulin Secretory Responses to Mixed Meal. J Clin Endocrinol Metab. 2007 Sep 25; [Epub ahead of print

49. Increased postprandial GIP and glucagon responses, but unaltered GLP-1 response after intervention with steroid hormone, relative physical inactivity, and high-calorie diet in healthy subjects J Clin Endocrinol Metab. 2011 Feb;96(2):447-53

50.  Resveratrol increases glucose induced GLP-1 secretion in mice: a mechanism which contributes to the glycemic control PLoS One. 2011;6(6):e20700.

51. Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases Cell 10.1016/j.cell.2012.01.017

52. Renal catabolism of human glucagon-like peptides 1 and 2. Can J Physiol Pharmacol. 1990 Dec;68(12):1568-73

53. Secretion, Degradation, and Elimination of Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide in Patients with Chronic Renal Insufficiency and Healthy Control Subjects. Diabetes. 2004 Mar;53(3):654-662.